Abstract: A comprehensive spatial picture of transcription in the nucleus Abstract: The DNA in a single human cell, if fully elongated, would stretch for roughly two meters. Yet the cell compacts these incredible long polymeric molecules within the cell's nucleus, typically just a few microns across. Increasingly, researchers are finding that the form this compaction takes is not just a random ""ball of string"" but rather is highly organized and dynamically regulated. However, there is no overall picture of how this organization affects gene expression. Our vision is to generate a comprehensive, quantitative understanding of the spatial organization of gene expression in the nucleus. We expect that the spatial control of chromosome structure is a critical regulating feature controlling gene expression, influencing variability in gene expression from cell to cell, and can even provide a structural basis for the coordination of gene network modules within the nucleus. Through the development of new experimental tools in combination with computational and analytical frameworks, our results will provide a new basis for incorporating spatial information in our understanding of the regulation and organization of genetic information. This newfound knowledge will greatly expand our understanding of the role spatial organization of gene expression plays in disease. Public Health Relevance: The work outlined in this proposal will greatly enhance our understanding of how the physical organization of the genetic code is related to cellular function. Genetic structure plays a key role in diseases such as cancer, and we anticipate our results will lead to the development of new diagnostic tools and potentially serve as markers for screening new therapeutic drugs.